The object of the experiments is to determine the amount of variation of structural genes in populations. This problem is attacked at the level of proteins by sequencing Alpha-glycerophosphate dehydrogenase protein from many isogenic lines of Drosophila from natural populations to look for amino acid substitutions not detectable by electrophoresis. At the level of the gene, the investigation is the sequencing of the DNA of the alcohol dehydrogenase gene from isogenic lines of Drosophila melanogaster from widely separated populations. Comparison will be made between variation of introns and exons, variation of non-redundant with redundant code changes. A related set of experiments involves the calibration of gel electrophoresis as a method for detecting protein variation. Known amino acid substitutions in the lac repressor molecule and tryptophane synthetase of E. coli will be subject to sequential electrophoresis to determine the sensitivity of this widely used method to chemically similar substitutions. The kinds of genetic variation in enzyme molecules present in populations is of direct interest to problems of genetic disease and to variation in reactions to drugs and environmental stress.